The ATF6-EGF Pathway Mediates the Awakening of Slow-Cycling Chemoresistant Cells and Tumor Recurrence by Stimulating Tumor Angiogenesis.

Jaebeom Cho,Xuan Wei,Ho-Young Lee,Shin-Hyung Park,Hye-Young Min,Sungyoul Hong,Honglan Pei,Su Jung Hwang,Young Kee Shin,Hyo-Jong Lee,Jeong Yeon Sim

doi:10.3390/cancers12071772

Abstract

Slow-cycling cancer cells (SCCs) with a quiescence-like phenotype are believed to perpetrate cancer relapse and progression. However, the mechanisms that mediate SCC-derived tumor recurrence are poorly understood. Here, we investigated the mechanisms underlying cancer recurrence after chemotherapy, focusing on the interplay between SCCs and the tumor microenvironment. We established a preclinical model of SCCs by exposing non-small-cell lung cancer (NSCLC) cells to either the proliferation-dependent dye carboxyfluorescein diacetate succinimidyl ester (CFSE) or chemotherapeutic drugs. An RNA sequencing analysis revealed that the established SCCs exhibited the upregulation of a group of genes, especially epidermal growth factor (EGF). Increases in the number of vascular endothelial growth factor receptor (VEGFR)-positive vascular endothelial cells and epidermal growth factor receptor (EGFR) activation were found in NSCLC cell line- and patient-derived xenograft tumors that progressed upon chemotherapy. EGFR tyrosine kinase inhibitors effectively suppressed the migration and tube formation of vascular endothelial cells. Furthermore, activating transcription factor 6 (ATF6) induced the upregulation of EGF, and its antagonism effectively suppressed these SCC-mediated events and inhibited tumor recurrence after chemotherapy. These results suggest that the ATF6-EGF signaling axis in SCCs functions to trigger the angiogenesis switch in residual tumors after chemotherapy and is thus a driving force for the switch from SCCs to actively cycling cancer cells, leading to tumor recurrence.

Highlights

Despite great advances in its diagnosis and treatment, cancer is the leading cause of death worldwide [1]
We found that established slow-cycling/dormant cancer cells (SCCs) exhibited the transcriptional upregulation of epidermal growth factor (EGF) through the activation of the activating transcription factor 6 (ATF6)-unfolded protein response (UPR) branch, which, in turn, stimulated angiogenesis in residual tumors after chemotherapy
Immunohistochemistry (IHC) analyses showing the recruitment of vascular endothelial cells (VEGFR2+ ) and endothelial progenitor cells (CD133+ ) in tumors that progressed after chemotherapy

Summary

Introduction

Despite great advances in its diagnosis and treatment, cancer is the leading cause of death worldwide [1]. Cancers 2020, 12, 1772 therapy, and immunotherapy—have been developed and are used in the clinic [2], many cancer patients eventually develop tumor relapse, the major cause of cancer-related death [3]. Non-small cell lung cancer (NSCLC), which accounts for 80–85% of lung cancer cases [4], is not an exception. To improve the prognosis of NSCLC patients, it is important to better understand the biology of cancer recurrence and develop efficacious strategies to suppress disease progression. Since most chemotherapeutics target highly proliferating cancer cells [8], a small population of dormant cancer cells in minimal residual disease is believed to cause tumor recurrence [10,11]

Objectives

Methods

Results

Discussion

Conclusion